tbuckley/cabot-search huggingface dataset:
Analysis of a Sabin-Strain Inactivated Poliovirus Vaccine Response to a Circulating Type 2 Vaccine-Derived Poliovirus Event in Sichuan Province, China 2019-2021
Authors: Hong Yang, Qi Qi, Yong Zhang, Ning Wen, Lei Cao, Yu Liu, Chunxiang Fan, Dongmei Yan, Xiaoping Zhu, Lixin Hao, Shuangli Zhu, Qianli Ma, Jiajie Liu, Chao Ma, Lei Nan, Yong Chen, Xiaozhen Ma, Na Chen, Kun Deng, Ge Shao, Xianxiang Ding, Zhijie An, Lance E. Rodewald, Xiaolei Li, Dongyan Wang, Hui Zhu, Huaqing Wang, Zijian Feng, Wenbo Xu, Jiushun Zhou, Zundong Yin, Weizhong Yang, Qun Li, Huiming Luo, Aiqiang Xu, Fang Fang
Journal: JAMA Network Open (2023)

Importance The Sabin-strain inactivated poliovirus vaccine (IPV) may be a tool for polio outbreak response in certain situations. Objective To investigate the response to a type 2 vaccine-derived poliovirus (VDPV2) outbreak. Design, Setting, and Participants This case series was conducted in China after a VDPV2 was detected in stool specimens from a child with acute flaccid paralysis (AFP) in Sichuan Province in 2019, 3 years after the global withdrawal of live, attenuated type 2 oral poliovirus vaccine (OPV). Investigation followed National Health Commission and World Health Organization guidance and included searching hospitals for unreported AFP cases; testing stool specimens from the child, his contacts, and local children; enhanced environmental surveillance for VDPV2s in wastewater; and measuring vaccination coverage. Sabin-strain IPV campaigns were conducted in a wide geographic area. Main Outcomes and Measures Any VDPV2 detection after completion of the supplementary immunization activities. Results A 28-nucleotide-change VDPV2 was isolated from a young boy. Three VDPV2s were detected in healthy children; 2 were contacts of the original child, and none had paralysis. A search of 31 million hospital records found 10 unreported AFP cases; none were polio. No type 2 polioviruses were found in wastewater. Prior to the event, polio vaccine coverage was 65% among children younger than 5 years. Sabin-strain IPV campaigns reached more than 97% of targeted children, administering 1.4 million doses. No transmission source was identified. More than 1 year of enhanced poliovirus environmental and AFP surveillance detected no additional VDPVs. Conclusions and Relevance These findings suggest that the circulating VPDV2 outbreak in 2019 was associated with low vaccine coverage. An investigation discovered 3 infected but otherwise healthy children and no evidence of the virus in wastewater. Following Sabin-strain IPV–only campaigns expanding from county to prefecture, the poliovirus was not detected, and the outbreak response was considered by an expert panel and the World Health Organization to have been successful. This success suggests that the Sabin-strain IPV may be a useful tool for responding to circulating VDPV2 outbreaks when high-quality supplementary immunization activities can be conducted and carefully monitored in settings with good sanitation.
Prognostic and Predictive Value of Immune-Related Gene Expression Signatures vs Tumor-Infiltrating Lymphocytes in Early-Stage ERBB2/HER2-Positive Breast Cancer
Authors: Aranzazu Fernandez-Martinez, Tomás Pascual, Baljit Singh, Paolo Nuciforo, Naim U. Rashid, Karla V. Ballman, Jordan D. Campbell, Katherine A. Hoadley, Patricia A. Spears, Laia Pare, Fara Brasó-Maristany, Nuria Chic, Ian Krop, Ann Partridge, Javier Cortés, Antonio Llombart-Cussac, Aleix Prat, Charles M. Perou, Lisa A. Carey
Journal: JAMA Oncology (2023)

Both tumor-infiltrating lymphocytes (TILs) assessment and immune-related gene expression signatures by RNA profiling predict higher pathologic complete response (pCR) and improved event-free survival (EFS) in patients with early-stage ERBB2/HER2-positive breast cancer. However, whether these 2 measures of immune activation provide similar or additive prognostic value is not known.
The Biology of Pain: Through the Rheumatology Lens
Authors: Flavia Sunzini, Andrew Schrepf, Daniel J. Clauw, Neil Basu
Journal: Arthritis & Rheumatology (2023)

Chronic pain is a major socioeconomic burden globally. The most frequent origin of chronic pain is musculoskeletal. In inflammatory musculoskeletal diseases such as rheumatoid arthritis (RA), chronic pain is a primary determinant of deleterious quality of life. The pivotal role of peripheral inflammation in the initiation and perpetuation of nociceptive pain is well‐established among patients with musculoskeletal diseases. However, the persistence of pain, even after the apparent resolution of peripheral inflammation, alludes to the coexistence of different pain states. Recent advances in neurobiology have highlighted the importance of nociplastic pain mechanisms. In this review we aimed to explore the biology of pain with a particular focus on nociplastic pain in RA.
Physician Men Leaders in Emergency Medicine Bearing Witness to Gender-Based Discrimination
Authors: Maya S. Iyer, Kalah Wilson, Claire Draucker, Cherri Hobgood
Journal: JAMA Network Open (2023)

Approximately 60% of women physicians in emergency medicine (EM) experience gender-based discrimination (GBD). Women physicians are also more likely to experience GBD than men physicians, particularly from patients, other physicians, or nursing staff.To describe the responses of men who are academic department chairs in EM to GBD directed toward a woman colleague.This qualitative study was a secondary data analysis drawn from interviews of men EM academic department chairs at 18 sites who participated in a qualitative descriptive study between April 2020 and February 2021 on their perceptions of the influence of gender and leadership in academic medicine. Narrative data related to GBD were extracted and coded using conventional content analysis. Codes were clustered into themes and subthemes and summarized. Data were analyzed from November to December 2021.Semistructured interviews conducted via teleconferencing.Qualitative findings identifying experiences witnessing or learning about incidents of GBD against women colleagues, the impact of these observations, and personal or leadership actions taken in response to their observations.All 18 men participants (mean [SD] age, 52.2 [7.5] years; mean [SD] time as a department chair, 7.2 [5.1] years) discussed witnessing or learning about incidents of GBD against women colleagues. The participant narratives revealed 3 themes: emotional responses to GBD, actions they took to address GBD, and reasons for not taking action to address GBD. When witnessing GBD, participants felt anger, disbelief, guilt, and shame. To take action, they served as upstanders, confronted and reported discrimination, provided faculty development on GBD, or enforced "zero-tolerance" policies. At times they did not take action because they did not believe the GBD warranted a response, perceived a power differential or an unsupportive institutional culture, or sought self-preservation.In this qualitative study of men physician leaders, we found all participants reported feeling troubled by GBD against women colleagues and, if possible, took action to address the discrimination. At times they did not take action because of unsupportive workplace cultures. These findings suggest that institutional culture change that supports the interventions of upstanders and does not tolerate GBD is needed.
Inhibition of CD82 improves colitis by increasing NLRP3 deubiquitination by BRCC3
Authors: Jae-Sung Kim, Hyo Keun Kim, Joongho Lee, Sein Jang, Euni Cho, Seok-Jun Mun, Seokhyun Yoon, Chul-Su Yang
Journal: Cellular and Molecular Immunology (2023)
Treatment of Gestational Diabetes Mellitus and Maternal Risk of Diabetes After Pregnancy
Authors: Ravi Retnakaran, Chang Ye, Anthony J. Hanley, Philip W. Connelly, Mathew Sermer, Bernard Zinman
Journal: Diabetes Care (2023)

OBJECTIVE To compare postpartum glucose tolerance between women treated for gestational diabetes mellitus (GDM) and those not treated. RESEARCH DESIGN AND METHODS Metabolic testing was performed at 3 and 12 months postpartum in 599 women comprising the following gestational glucose tolerance groups: 1) normal glucose challenge test (GCT) and oral glucose tolerance test (OGTT) during pregnancy, 2) abnormal GCT with normal OGTT, 3) gestational impaired glucose tolerance, 4) mild untreated GDM, and 5) severe treated GDM. RESULTS Birth weight progressively increased across groups 1–4 before falling steeply in treated GDM (P &amp;lt; 0.0001). In contrast, at 3 and 12 months, insulin sensitivity and β-cell function progressively decreased across the five groups, mirrored by rising fasting and 2-h glucose (all P &amp;lt; 0.0001). Accordingly, prevalence of prediabetes/diabetes at 12 months increased in a stepwise manner across groups 1–5 (2.8%, 9.6%, 13.5%, 21.5%, and 32.6%, respectively; P &amp;lt; 0.0001). CONCLUSIONS Treating GDM lowers birth weight but does not disrupt the association between gestational glycemia and maternal prediabetes/diabetes after pregnancy.
METTL5 stabilizes c‐Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression
Authors: Peng Xia, Hao Zhang, Haofeng Lu, Kequan Xu, Xiang Jiang, Yuke Jiang, Xiangdong Gongye, Zhang Chen, Jie Liu, Xi Chen, Weijie Ma, Zhonglin Zhang, Yufeng Yuan
Journal: Cancer Communications (2023)

Abstract Background Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, with a high likelihood of metastasis and a dismal prognosis. The reprogramming of glucose metabolism is critical in the development of HCC. The Warburg effect has recently been confirmed to occur in a variety of cancers, including HCC. However, little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells. In this study, we sought to better understand how methyltransferase 5, N6‐adenosine (METTL5) controls the development of HCC and the Warburg effect. Methods In the current study, quantitative real‐time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines. Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecular mechanism of HCC. Glutathione‐S‐transferase pulldown, coimmunoprecipitation, RNA sequencing, non‐targeted metabolomics, polysome profiling, and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells. Results We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC. Mechanistically, upregulation of METTL5 promoted c‐Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A ( LDHA ), enolase 1 ( ENO1 ), triosephosphate isomerase 1 ( TPI1 ), solute carrier family 2 member 1 ( SLC2A1 ), and pyruvate kinase M2 ( PKM2 ). The c‐Box and ubiquitin binding domain (UBA) regions of ubiquitin specific peptidase 5 (USP5) binded to c‐Myc protein and inhibited K48‐linked polyubiquitination of c‐Myc. Further study revealed that METTL5 controled the USP5 translation process, which in turn regulated the ubiquitination of c‐Myc. Furthermore, we identified cAMP responsive element binding protein 1 (CREB1)/P300 as a critical transcriptional regulator of METTL5 that promoted the transcription of METTL5 in HCC. In patient‐derived tumor xenograft (PDX) models, adenovirus‐mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX‐bearing mice. Conclusions These findings point to a novel mechanism by which CREB1/P300‐METTL5‐USP5‐c‐Myc controls abnormal glucose metabolism and promotes tumor growth, suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.
Adoption of Innovative Therapies Across Oncology Practices—Evidence From Immunotherapy
Authors: Caitlin E. Carroll, Mary Beth Landrum, Alexi A. Wright, Nancy L. Keating
Journal: JAMA Oncology (2023)

Importance Immunotherapies reflect an important breakthrough in cancer treatment, substantially improving outcomes for patients with a variety of cancer types, yet little is known about which practices have adopted this novel therapy or the pace of adoption. Objective To assess adoption of immunotherapies across US oncology practices and examine variation in adoption by practice type. Design, Setting, and Participants This cohort study used data from Medicare fee-for-service beneficiaries undergoing 6-month chemotherapy episodes between 2010 and 2017. Data were analyzed January 19, 2021, to September 28, 2022, for patients with cancer types for which immunotherapy was approved by the US Food and Drug Administration (FDA) during the study period: melanoma, kidney cancer, lung cancer, and head and neck cancer. Exposures Oncology practice location (rural vs urban), affiliation type (academic system, nonacademic system, independent), and size (1 to 5 physicians vs 6 or more physicians). Main Outcomes and Measures The primary outcome was whether a practice adopted immunotherapy. Adoption rates for each practice type were estimated using multivariate linear models that adjusted for patient characteristics (age, sex, race and ethnicity, cancer type, Charlson Comorbidity Index, and median household income). Results Data included 71 659 episodes at 1732 oncology practices. Of these, 264 practices (15%) were rural, 900 (52%) were independent, and 492 (28%) had 1 to 5 physicians. Most practices adopted immunotherapy within 2 years of FDA approval, but there was substantial variation in adoption rates across practice types. After FDA approval, adoption of immunotherapy was 11 (95% CI, −16 to −6) percentage points lower at rural practices than urban practices and 27 (95% CI, −32 to −22) percentage points lower at practices with 1 to 5 physicians than practices with 6 or more physicians. Adoption rates were similar at independent practices and nonacademic systems; however, both practice types had lower adoption than academic systems (independent practice difference, −6 [95% CI, −9 to −3] percentage points; nonacademic systems difference, −9 [95% CI, −11 to −6] percentage points). Conclusions and Relevance In this cohort study of Medicare claims, practice characteristics, especially practice size and rural location, were associated with adoption of immunotherapy. These findings suggest that there may be geographic disparities in access to important innovations for treating patients with cancer.
Effect of Cellular and Microenvironmental Multidrug Resistance on Tumor-Targeted Drug Delivery in Triple-Negative Breast cancer
Authors: Okan Tezcan, Asmaa Said Elshafei, Karina Benderski, Elena Rama, Maike Wagner, Diana Moeckel, Robert Pola, Michal Pechar, Tomas Etrych, Saskia von Stillfried, Fabian Kiessling, Ralf Weiskirchen, Steffen Meurer, Twan Lammers
Journal: Journal of Controlled Release (2023)
Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models
Authors: Elizabeth R. Tucker, Irene Jiménez, Lindi Chen, Angela Bellini, Chiara Gorrini, Elizabeth Calton, Qiong Gao, Harvey Che, Evon Poon, Yann Jamin, Barbara Martins Da Costa, Karen Barker, Sumana Shrestha, J. Ciaran Hutchinson, Simran Dhariwal, Angharad Goodman, Elaine Del Nery, Pierre Gestraud, Jaydutt Bhalshankar, Yasmine Iddir, Elnaz Saberi-Ansari, Alexandra Saint-Charles, Birgit Geoerger, Maria Eugénia Marques Da Costa, Cécile Pierre-Eugène, Isabelle Janoueix-Lerosey, Didier Decaudin, Fariba Nemati, Angel M. Carcaboso, Didier Surdez, Olivier Delattre, Sally L. George, Louis Chesler, Deborah A. Tweddle, Gudrun Schleiermacher
Journal: Clinical Cancer Research (2023)

ALK-activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1%-2% of cases. Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single-agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data have suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway.We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin, and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient-derived xenografts (PDX).Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX, lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth.In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma.
CXCR5+PD-1++ CD4+ T cells colonize infant intestines early in life and promote B cell maturation
Authors: Ana Jordan-Paiz, Glòria Martrus, Fenja L. Steinert, Max Kaufmann, Adrian F. Sagebiel, Renée R. C. E. Schreurs, Anne Rechtien, Martin E. Baumdick, Johannes M. Jung, Kimberly J. Möller, Lucy Wegner, Cordula Grüttner, Laura Richert, Roland Thünauer, Jennifer Schroeder-Schwarz, Johannes B. van Goudoever, Teunis B. H. Geijtenbeek, Marcus Altfeld, Steven T. Pals, Daniel Perez, Paul L. Klarenbeek, Christian Tomuschat, Guido Sauter, Ingo Königs, Udo Schumacher, Manuel A. Friese, Nathaniel Melling, Konrad Reinshagen, Madeleine J. Bunders
Journal: Cellular and Molecular Immunology (2023)
A systems biology approach identifies the role of dysregulated PRDM6 in the development of hypertension
Authors: Kushan L. Gunawardhana, Lingjuan Hong, Trojan Rugira, Severin Uebbing, Joanna Kucharczak, Sameet Mehta, Dineth R. Karunamuni, Brenda Cabera-Mendoza, Neeru Gandotra, Curt Scharfe, Renato Polimanti, James P. Noonan, Arya Mani
Journal: Journal of Clinical Investigation (2023)

Genetic variants in the third intron of the PRDM6 gene have been associated with BP traits in multiple GWAS. By combining fine mapping, massively parallel reporter assays, and gene editing, we identified super enhancers that drive the expression of PRDM6 and are partly regulated by STAT1 as the causal variants for hypertension. The heterozygous disruption of Prdm6 in mice expressing Cre recombinase under the control of mouse smooth muscle cell protein 22-α promoter (Prdm6fl/+ SM22-Cre) exhibited a markedly higher number of renin-producing cells in the kidneys at E18.5 compared with WT littermates and developed salt-induced systemic hypertension that was completely responsive to the renin inhibitor aliskiren. Strikingly, RNA-Seq analysis of the mouse aortas identified a network of PRDM6-regulated genes that are located in GWAS-associated loci for blood pressure, most notably Sox6, which modulates renin expression in the kidney. Accordingly, the smooth muscle cell–specific disruption of Sox6 in Prdm6fl/+ SM22-Cre mice resulted in a dramatic reduction of renin. Fate mapping and histological studies also showed increased numbers of neural crest–derived cells accompanied by increased collagen deposition in the kidneys of Prdm6fl/+ Wnt1Cre-ZsGreen1Cre mice compared with WT mice. These findings establish the role of PRDM6 as a regulator of renin-producing cell differentiation into smooth muscle cells and as an attractive target for the development of antihypertensive drugs.
Assessment of systemic AAV-microdystrophin gene therapy in the GRMD model of Duchenne muscular dystrophy
Authors: Sharla M. Birch, Michael W. Lawlor, Thomas J. Conlon, Lee-Jae Guo, Julie M. Crudele, Eleanor C. Hawkins, Peter P. Nghiem, Mihye Ahn, Hui Meng, Margaret J. Beatka, Brittany A. Fickau, Juan C. Prieto, Martin A. Styner, Michael J. Struharik, Courtney Shanks, Kristy J. Brown, Diane Golebiowski, Amanda K. Bettis, Cynthia J. Balog-Alvarez, Nathalie Clement, Kirsten E. Coleman, Manuela Corti, Xiufang Pan, Stephen D. Hauschka, J. Patrick Gonzalez, Carl A. Morris, Joel S. Schneider, Dongsheng Duan, Jeffrey S. Chamberlain, Barry J. Byrne, Joe. N. Kornegay
Journal: Science Translational Medicine (2023)

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, a membrane-stabilizing protein encoded by the DMD gene. Although mouse models of DMD provide insight into the potential of a corrective therapy, data from genetically homologous large animals, such as the dystrophin-deficient golden retriever muscular dystrophy (GRMD) model, may more readily translate to humans. To evaluate the clinical translatability of an adeno-associated virus serotype 9 vector (AAV9)–microdystrophin (μDys5) construct, we performed a blinded, placebo-controlled study in which 12 GRMD dogs were divided among four dose groups [control, 1 × 10 13 vector genomes per kilogram (vg/kg), 1 × 10 14 vg/kg, and 2 × 10 14 vg/kg; n = 3 each], treated intravenously at 3 months of age with a canine codon-optimized microdystrophin construct, rAAV9-CK8e-c-μDys5, and followed for 90 days after dosing. All dogs received prednisone (1 milligram/kilogram) for a total of 5 weeks from day −7 through day 28. We observed dose-dependent increases in tissue vector genome copy numbers; μDys5 protein in multiple appendicular muscles, the diaphragm, and heart; limb and respiratory muscle functional improvement; and reduction of histopathologic lesions. As expected, given that a truncated dystrophin protein was generated, phenotypic test results and histopathologic lesions did not fully normalize. All administrations were well tolerated, and adverse events were not seen. These data suggest that systemically administered AAV-microdystrophin may be dosed safely and could provide therapeutic benefit for patients with DMD.
Clonally expanded HIV-1 proviruses with 5′-leader defects can give rise to nonsuppressible residual viremia
Authors: Jennifer A. White, Fengting Wu, Saif Yasin, Milica Moskovljevic, Joseph Varriale, Filippo Dragoni, Angelica Camilo-Contreras, Jiayi Duan, Mei Y. Zheng, Ndeh F. Tadzong, Heer B. Patel, Jeanelle Mae C. Quiambao, Kyle Rhodehouse, Hao Zhang, Jun Lai, Subul A. Beg, Michael Delannoy, Christin Kilcrease, Christopher J. Hoffmann, Sébastien Poulin, Frédéric Chano, Cécile Tremblay, Jerald Cherian, Patricia Barditch-Crovo, Natasha Chida, Richard D. Moore, Michael F. Summers, Robert F. Siliciano, Janet D. Siliciano, Francesco R. Simonetti
Journal: Journal of Clinical Investigation (2023)

Background. Antiretroviral therapy (ART) halts HIV-1 replication, decreasing viremia to below the detection limit of clinical assays. However, some individuals experience persistent nonsuppressible viremia (NSV) originating from CD4+ T cell clones carrying infectious proviruses. Defective proviruses represent over 90% of all proviruses persisting during ART and can express viral genes, but whether they can cause NSV and complicate ART management is unknown.
INPP5K controls the dynamic structure and signaling of wild-type and mutated, leukemia-associated IL-7 receptors
Authors: Bastien Moës, Hua Li, Patricia Molina-Ortiz, Coraline Radermecker, Adeline Rosu, Charles-Andrew Vande Catsyne, Sufyan Ali Sayyed, João Fontela, Mafalda Duque, Alice Mostafa, Abdelhalim Azzi, João T. Barata, Ramon Merino, Chenqi Xu, Christophe J. Desmet, Stéphane Schurmans
Journal: Blood (2023)